Summary:
P21WAF1/CIP1 is a universal cyclin-dependent kinase inhibitor and plays a
crucial role in the DNA damage response (DDR) pathway. P21WAF1/CIP1 is a
multifunctional molecule whose role in carcinogenesis as a tumor-suppressor is
being disputed. In this study, there was used the doxycycline inducible cell
system Saos2-p21WAF1/CIP1 Τet ON and there was conducted a gel-free iTRAQ
proteomic analysis at three different time points, i.e. 12, 48 and 96 hrs after
the induction of p21WAF1/CIP1
in order to investigate the effects of the long-term expression of p21WAF1/CIP1
in a p53 null background. Proteomics combined with bioinformatics indicated
that the proteins which are mostly affected by p21WAF1/CIP1 are those
associated with DNA replication (up-regulation) and mitotis-associated ones
(down-regulation). Given that deregulation of the mitotic machinery along with
disturbed control of genome replication have been linked to the triggering of
genomic instability, the results pay credit to the notion that p21WAF1/CIP1
exhibits a “vicious” pro-tumorigenic facet.
On the other hand, ΑRF (alternative reading frame) is also a tumor-suppressive
protein, being assigned with multiple intracellular duties. Recently, there was
demonstrated an interrelation among the DDR kinase ATM and ARF. Here, there
were applied a series of molecular and in situ techniques as well as
bioinformatics in order to identify a possible interplay among ARF and the
ATM-related kinase ATR or even among ARF and the DDR component MKK7. Further,
there were analyzed xenografts in mice in order to characterize the
anti-angiogenic activity of ARF when ATM is suppressed. The resulting data
indicate that ARF participates in a perplexed network of signaling
relationships within the DDR landscape and that ATM suppression may be
harnessed as a novel anti-angiogenic strategy in p53-deficient tumors.
